Leukotriene B4 derivatives, in particular oximo-LTB4 - antagonists

ABSTRACT

Leukotriene-B 4  derivatives of general formula (I), in which R 1  represents H, CF 3 , CH 2  OH, and R 2  represents H or an organic acid radical; R 3  symbolizes H, C 1  -C 14  alkyl, C 3  -C 10  cycloalkyl, or a 5- to 6-membered aromatic heterocyclic ring with at least 1 heteroatom; R 4  means hydrogen, C 1  -C 10  alkyl, C 3  -C 10  cycloalkyl; A symbolizes a trans, trans--CH═CH--CH═CH, a --CH 2  CH 2  --CH═CH-- or a tetramethylene group; B symbolizes a C 1  -C 10  -- straight-chain or branched-chain alkylene group or group (a) or (b); D can mean a direct bond, oxygen, sulfur, --C.tbd.C--, --CH═CR 7 , or together with B can also mean a direct bond; R 5  and R 6  are the same or different and represent H or C 1  -C 4  alkyl, or R 6  represents H and R 5  represents C 1  -C 15  alkanoyl or R 8  represents SO 2  ; R 7  means H, C 1  -C 5  alkyl, chlorine, bromine; R 8  has the same meaning as R 3 , m means 1-3, o means 0-5, p means 0-5, X is a direct bond, oxygen, sulfur, an aromatic compound or heteroaromatic compound, Y is a C 1  -C 8  alkyl, C 3  -C 10  cycloalkyl, n is 2-5, and, if R 4  means hydrogen, their salts with physiologically compatible bases and their cyclodextrin clathrates. The leukotriene derivatives are used as dermatological products. ##STR1##

The invention relates to new leukotriene-B₄ derivatives, process fortheir production and their use as pharmaceutical agents. The newcompounds are optically active structural analogues of previously knownleukotriene-B₄ antagonists, which contain a six-membered ring as a basicstructural element (DE-A 39 17 597, DE-A 42 27 790.6, DE 42 42 390).##STR2## KEY: Arachidonsaure=arachidonic acid

Leukotrien A₄ (LTA₄)=leukotriene A₄ (LTA₄)

Glutathion-S-transferase=glutathione-S-transferase

Leukotrien B₄ (LTB₄)=leukotriene B₄ (LTB₄)

Leukotrien C₄ (LTC₄)=leukotriene C₄ (LTC₄)

Leukotriene B₄ (LTB₄) was discovered by B. Samuelsson et al. as ametabolite of the arachidonic acid. In the biosynthesis, leukotriene A₄is formed by the enzyme 5-lipoxygenase first as a central intermediateproduct, which then is converted by a specific hydrolase into the LTB₄.

The nomenclature of the leukotrienes can be deduced from the followingworks:

a) B. Samuelsson et al., Prostaglandins 19, 654 (1980); 17, 785 (1979).

b) C. N. Serhan et al., Prostaglandins 34, 201 (1987).

The physiological and especially the pathophysiological importance ofleukotriene B₄ is summarized in several more recent works: a) TheLeukotrienes, Chemistry and Biology eds. L. W. Chakrin, D. M. Bailey,Academic Press 1984. b) J. W. Gillard et al., Drugs of the Future 12,453 (1987). c) B. Samuelsson, Sciences 237, 1171 (1987). d) C. W.Parker, Drug Development Research 10, 277 (1987). e) W. R. Henderson,Annals of Internal Medicine 121, 684 (1994). It follows from the abovethat LTB₄ is an important inflammation mediator for inflammatorydiseases, in which leukocytes invade the affected tissue.

The effects of LTB₄ are triggered on the cellular plane by the bindingof LTB₄ to a specific receptor.

It is known concerning LTB₄ that it causes the adhesion of leukocytes tothe blood vessel wall. LTB₄ is chemotactically active, i.e., it triggersa directed migration of leukocytes in the direction of a gradient ofincreasing concentration. Furthermore, it indirectly changes thevascular permeability based on its chemotactic activity, whereby asynergism with prostaglandin E₂ is observed. LTB₄ obviously plays adecisive role in inflammatory, allergic and immunological processes.

Leukotrienes and especially LTB₄ are involved in skin diseases, whichare accompanied by inflammatory processes (increased vascularpermeability and formation of edemas, cell infiltration), increasedproliferation of skin cells and itching, such as, for example, ineczemas, erythemas, psoriasis, pruritus and acne. Pathologicallyincreased leukotriene concentrations are involved either causally in thedevelopment of many dermatitides or there is a connection between thepersistence of the dermatitides and the leukotrienes. Clearly increasedleukotriene concentrations were measured, for example, in the skin ofpatients with psoriasis, atopic dermatitis, allergic contact dermatitis,bullous pemiphigoids, delayed duchurticaria and allergic vasculitis.

Leukotrienes and especially LTB₄ are also involved in the diseases ofinternal organs, for which an acute or chronic inflammatory componentwas described, e.g.: joint diseases (rheumatic arthritis); diseases ofthe respiratory tract (asthma and chronically obstructive lung diseases(OPD)); inflammatory intestinal diseases (ulcerous colitis and Crohn'sdisease); as well as reperfusion damages (to the heart, intestinal orrenal tissues), which result by the temporary pathological obstructionof blood vessels, such as glomerulonephritis, NSAID gastropathies,multiple sclerosis, rhinitis and inflammatory eye diseases.

Further, leukotrienes and especially LTB₄ are involved in the disease ofmultiple sclerosis and in the clinical appearance of shock (triggered byinfections, burns or in complications in kidney dialysis or otherseparately discussed perfusion techniques).

In addition, leukotrienes and especially LTB₄ have an effect on theformation of white blood cells in the bone marrow, on the growth ofunstriped muscle cells, of keratinocytes and of B-lymphocytes. LTB₄ istherefore involved in diseases with inflammatory processes and indiseases with pathologically increased formation and growth of cells.

For example, leukemia or arteriosclerosis represent diseases with thisclinical appearance.

Leukotrienes and especially LTB₄ and its derivatives are suitable forreducing elevated triglyceride levels and thus act in ananti-arteriosclerotic manner and against obesity.

By the antagonizing of the effects, especially by LTB₄, the activeingredients and their forms for dispensing of this invention arespecific medicines for diseases of humans and animals, in whichespecially leukotrienes play a pathological role.

Besides the therapeutic possibilities, which can be derived from anantagonizing of LTB₄ action with LTB₄ analogs, the usefulness andpotential use of leukotriene-B₄ agonists for the treatment of fungusdiseases of the skin were also able to be shown (H. Katayama,Prostaglandins 34, 797 (1988)).

The invention relates to leukotriene-B₄ derivatives of general formula I##STR3## in which R₁ represents H, CF₃, CH₂ OH, COOR₄, CONR₅ R₆, and

R₂ represents H or an organic acid radical with 1-15 C atoms,

R₃ symbolizes H; C₁ -C₁₄ alkyl, C₃ -C₁₀ cycloalkyl optionallysubstituted in one or more places; C₆ -C₁₀ aryl radicals, independentlyof one another, optionally substituted in one or more places by halogen,phenyl, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, fluoromethyl, chloromethyl,trifluoromethyl, carbonyl, carboxyl or hydroxyl; or a 5- to 6-memberedaromatic heterocyclic ring with at least 1 heteroatom,

R₄ means hydrogen, C₁ -C₁₀ alkyl, C₃ -C₁₀ cycloalkyl; C₆ -C₁₀ arylradicals optionally substituted by 1-3 halogen, phenyl, C₁ -C₄ alkyl, C₁-C₄ alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxyl orhydroxyl; CH₂ --CO--(C₆ -C₁₀) aryl or a 5- to 6-membered ring with atleast 1 heteroatom,

A symbolizes a trans, trans-CH═CH--CH═CH, a --CH₂ CH₂ --CH═CH-- or atetramethylene group,

B symbolizes a C₁ -C₁₀ straight-chain or branched-chain alkylene group,which optionally can be substituted by fluorine or the group ##STR4## Dmeans a direct bond, oxygen, sulfur, --C.tbd.C--, --CH═CR₇, or togetherwith B can also mean a direct bond,

R₅ and R₆ are the same or different, and represent H or C₁ -C₄ alkyloptionally substituted by hydroxy groups, or R₆ represents H and R₅represents C₁ -C₁₅ alkanoyl or R₈ SO₂,

R₇ means H, C₁ -C₅ alkyl, chlorine, bromine,

R₈ has the same meaning as R₃,

m means 1-3,

o means 0-5,

p means 0-4,

X is a direct bond, oxygen, sulfur, an aromatic compound orheteroaromatic compound,

Y is a C₁ -C₈ alkyl optionally substituted in one or more places, C₃-C₁₀ cycloalky, optionally substituted by aryl,

n is 2-5,

and, if R₄ means hydrogen, their salts with physiologically compatiblebases and their cyclodextrin clathrates.

The group OR₂ can be in α- or β-position. Formula I comprises bothracemates and the possible pure diastereomers and enantiomers. Thestereochemistry of the oxime double bond can be E- or Z-configured;preferably E-configured oximes are obtained.

As alkyl groups R₄, straight-chain or branched-chain alkyl groups with1-10 C atoms are considered, such as, for example, methyl, ethyl,propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl,decyl.

Alkyl groups R₄ can optionally be substituted in one or more places byhalogen atoms, alkoxy groups, optionally substituted aryl or aroylgroups with 6-10 C atoms (relative to possible substituents, see underaryl R₄), dialkylamino and trialkylammonium with 1-4 C atoms in thealkyl portion, whereby single substitution is to be preferred. Assubstituents, for example, fluorine, chlorine or bromine, phenyl,dimethylamino, diethylamino, methoxy, ethoxy can be mentioned. Aspreferred alkyl groups R₄, those with 1-4 C atoms can be mentioned.

Cycloalkyl group R₄ can contain 3-10, preferably 5 and 6 carbon atoms inthe ring. The rings can be substituted by alkyl groups with 1-4 carbonatoms. For example, cyclopentyl, cyclohexyl, methylcyclohexyl can bementioned.

As aryl groups R₄, both substituted and unsubstituted aryl groups with6-10 C atoms are considered, such as, for example, phenyl, 1-naphthyland 2-naphthyl, which can be substituted in each case by 1-3 halogenatoms (F, Cl, Br), a phenyl group, 1-3 alkyl groups with, in each case,1-4 C atoms, a chloromethyl, a fluoromethyl, trifluoromethyl, carboxyl,hydroxyl or alkoxy group with 1-4 C atoms. Preferred substituents in 3-and 4-position on the phenyl ring are, for example, fluorine, chlorine,alkoxy or trifluoromethyl, in 4-position, however, hydroxyl.

As heterocyclic groups R₄, 5- and 6-membered aromatic heterocycles thatcontain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur,are suitable. For example, 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, 3-furyl,3-thienyl, 2-tetrazolyl, i.a., can be mentioned.

As acid radical R₅, such physiologically compatible acids are suitable.Preferred acids are organic carboxylic acids and sulfonic acids with1-15 carbon atoms, which belong to the aliphatic, cycloaliphatic,aromatic, aromatic-aliphatic and heterocyclic series. These acids can besaturated, unsaturated and/or polybasic and/or substituted in the usualway. As examples of the substituents, C₁₋₄ alkyl, hydroxyl, C₁₋₄ alkoxy,oxo or amino groups or halogen atoms (F, Cl, Br) can be mentioned. Forexample, the following carboxylic acids can be mentioned: formic acid,acetic acid, propionic acid, butyric acid, isobutyric acid, valericacid, isovaleric acid, caproic acid, enanthic acid, caprylic acid,pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylicacid, myristic acid, pentadecylic acid, trimethylacetic acid,diethylacetic acid, tert-butylacetic acid, cyclopropylacetic acid,cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylicacid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid,methoxyacetic acid, ethoxyacetic acid, mono-, di- and trichloroaceticacid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid,morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoicacid; benzoic acids substituted with halogen (F, Cl, Br) ortrifluoromethyl, hydroxy, C₁₋₄ alkoxy or carboxy groups; nicotinic acid,isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid.As preferred arylsulfonyl radicals and alkanesulfonyl radicals R₈ SO₂,those are to be considered that are derived from a sulfonic acid with upto 10 carbon atoms. As sulfonic acids, for example, methanesulfonicacid, ethanesulfonic acid, isopropanesulfonic acid, cyclohexanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid,p-chlorobenzenesulfonic acid, N,N-dimethylaminosulfonic acid,N,N-diisobutylaminosulfonic acid, N,N-dibutylaminosulfonic acid,pyrrolidino, piperidino, piperazino, M-methylpiperazino andmorpholinosulfonic acid are suitable.

As alkyl groups R₃, straight-chain and branched-chain, saturated andunsaturated alkyl radicals, preferably saturated, with 1-14, especially1-10 C atoms, are suitable, which optionally can be substituted byoptionally substituted phenyl (for substitution, see under aryl R₅). Forexample, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl,hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, benzyl,m- and p-chlorobenzyl groups can be mentioned. If alkyl groups R₃ arehalogen-substituted, fluorine, chlorine and bromine are suitable ashalogens.

As examples of halogen-substituted alkyl groups R₃, alkyls with terminaltrifluoromethyl groups are considered.

Cycloalkyl group R₃ can contain 3-10, preferably 3-6 carbon atoms in thering. The rings can be substituted by alkyl groups with 1-4 carbon atomsoptionally by halogens. For example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, methyl-cyclohexyl, fluorocyclohexyl can bementioned.

As substituted or unsubstituted aryl groups R₃, for example, phenyl,1-naphthyl and 2-naphthyl, which can be substituted in each case by 1-3halogen atoms (F, Cl, Br), a phenyl group, 1-3 alkyl groups with 1-4 Catoms in each case, a chloromethyl, fluoromethyl, trifluoromethyl,carboxyl, C₁ -C₄ alkoxy or hydroxyl group, are considered. Preferred isthe substitution in 3- and 4-position on the phenyl ring by, forexample, fluorine, chlorine, alkoxy or trifluoromethyl or in 4-positionby hydroxyl.

As heterocyclic aromatic groups R₃, 5- and 6-membered heterocycles thatcontain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur,are suitable. For example, 2-furyl, 1-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl,3-furyl, 3-thienyl, i.a., can be mentioned.

As alkylene group B, straight-chain or branched, saturated orunsaturated alkylene radicals, preferably saturated with 1-10,especially with 1-5 C atoms, are suitable, which optionally can besubstituted by fluorine atoms. For example, methylene, fluoromethylene,difluoromethylene, ethylene, 1,2-propylene, ethylethylene, trimethylene,tetramethylene, pentamethylene, 1,2-difluoroethylene, 1-fluoroethylene,1-methyltetramethylene, 1-methyl-trimethylene, 1-methylene-ethylene,1-methylene-tetramethylene can be mentioned.

In addition, alkylene group B can represent the group ##STR5## wherebyn=2-5, preferably 3-5.

As acid radicals R₂, those of physiologically compatible acid radicalsare suitable. Preferred acids are organic carboxylic acids and sulfonicacids with 1-15 carbon atoms, which belong to the aliphatic,cycloaliphatic, aromatic, aromatic-aliphatic or heterocyclic series.These acids can be substituted saturated, unsaturated and/or polybasicand/or in the usual way. As examples of the substituents, C₁₋₄ alkyl,hydroxyl, C₁₋₄ alkoxy, oxo or amino groups or halogen atoms (F, Cl, Br)can be mentioned. For example, the following carboxylic acids can bementioned: formic acid, acetic acid, propionic acid, butyric acid,isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthicacid, caprylic acid, pelargonic acid, capric acid, undecylic acid,lauric acid, tridecylic acid, myristic acid, pentadecylic acid,trimethylacetic acid, diethylacetic acid, tert-butylacetic acid,cyclopentylacetic acid, cyclohexylacetic acid, cyclohexanecarboxylicacid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid,ethoxyacetic acid, mono-, di- and trichloroacetic acid, aminoaceticacid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoaceticacid, lactic acid, succinic acid, adipic acid, benzoic acid; benzoicacids substituted with halogen (F, Cl, Br) or trifluoromethyl, hydroxyl,C₁₋₄ alkoxy or carboxy groups; nicotinic acid, isonicotinic acid,furan-2-carboxylic acid, cyclopentylpropionic acid. As preferred acidradicals R₂ and R₃, those acyl radicals with up to 10 carbon atoms areconsidered.

Alkyl radicals R₅ and R₆, which optionally contain hydroxy groups, arestraight-chain or branched alkyl radicals, especially straight-chain,such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl,especially preferably methyl.

R₇ as C₁₋₅ alkyl means straight-chain or branched-chain alkyl radicalsas were already mentioned for R₃ or R₄. Preferred alkyl radicals R₇ aremethyl, ethyl, propyl and isopropyl.

Inorganic and organic bases are suitable for salt formation, as they areknown to one skilled in the art for forming physiologically compatiblesalts. For example, alkali hydroxides, such as sodium hydroxide andpotassium hydroxide, alkaline-earth hydroxides, such as calciumhydroxide, ammonia, amines, such as ethanolamine, diethanolamine,triethanolamine, N-methylglucamine, morpholine,tris(hydroxymethyl)-methylamine, etc., can be mentioned.

To attain the cyclodextrin clathrates, the compounds of formula I arereacted with α-, β- or γ-cyclodextrin. Preferred are β-cyclodextrinderivatives.

Preferred compounds of this invention are compounds of general formulaI, whereby the radicals have the following meaning:

R₁ is CF₃, CH₂ OH, CONR₅ R₆, COOR₄ with R₄ in the meaning of a hydrogenatom, an alkyl radical with 1-10 C atoms, a cycloalkyl radical with 5-6C atoms, a phenyl radical optionally substituted by 1-2 chlorine,bromine, phenyl, C₁₋₄ alkyl, C₁₋₄ alkoxy, chloromethyl, fluoromethyl,trifluoromethyl, carboxy or hydroxy,

X is an aromatic compound or a direct bond,

Y is a methyl group,

m is 1-3,

o is 1-5,

p is 0,1,

A is a trans-CH═CH--CH═CH or tetramethylene group;

B is a straight-chain or branched-chain, saturated or unsaturatedalkylene group with up to 10 C atoms, which optionally can besubstituted by fluorine, or the group ##STR6## with n=2-5; D is a directbond, oxygen, sulfur, a --C.tbd.C group or a --CH═CR₇ group with R₇ ashydrogen, C₁₋₅ alkyl, chlorine or bromine;

B and D are together a direct bond;

R₂ means hydrogen or an organic acid radical with 1-15 C atoms;

R₅ and R₆ have the above-indicated meanings;

R₃ is a hydrogen atom, C₁₋₁₀ alkyl, cycloalkyl with 5-6 C atoms, aphenyl radical optionally substituted by 1-2 chlorine, bromine, phenyl,C₁₋₄ alkyl, C₁₋₄ alkoxy, chloromethyl, fluoromethyl, trifluoromethyl,carboxyl or hydroxyl, and if

R₄ means a hydrogen, their salts with physiologically compatible basesand cyclodextrin clathrates.

Especially preferred compounds of this invention are compounds ofgeneral formula I, whereby the radicals have the following meaning:

R₁ is CF₃, CH₂ OH, CONR₅ R₆, COOR₄ with R₄ in the meaning of a hydrogenatom, an alkyl radical with 1-4 C atoms,

R₂ means hydrogen or an organic acid radical with 1-6 C atoms,

R₃ is a hydrogen atom or C₁₋₁₀ alkyl;

R₅ and R₆ have the above-indicated meanings;

A is a trans, trans-CH═CH--CH═CH or tetramethylene group;

B is a straight-chain or branched-chain alkylene group with up to 5 Catoms, or the group ##STR7## with n=3,4; D is a direct bond or a--C.tbd.C group or a --CH═CR₇ group with R₇ as hydrogen or C₁₋₅ alkyl;

X is a direct bond or an aromatic compound,

Y is a methyl group,

m is 2,

o is 1-5,

p is 0, 1,

B and D are together a direct bond;

and if R₄ means a hydrogen atom, their salts with physiologicallycompatible bases and their cyclodextrin clathrates.

In addition, the invention relates to a process for the production ofthe compounds of general formula I according to the invention, which ischaracterized in that a ketone of formula II, ##STR8## in which A, B, D,m, R₂, R₃ and Y have the above-indicated meaning, optionally underprotection of free hydroxy groups in R₂, is reacted with a hydroxylamineor a hydroxylammonium salt and then with an alkylating reagent ofgeneral formula III,

    E--(CH.sub.2).sub.o --X--(CH.sub.2).sub.p --R.sub.1        (III)

whereby E represents a halide or sulfonate, and o, X, p, and R₁ have theabove-indicated meanings, is reacted in the presence of a base andoptionally then separated in any sequence of isomers, protected hydroxygroups are released and/or a free hydroxy group is etherified and/or acarboxyl group is reduced and/or a carboxyl group is esterified and/or acarboxyl group is converted into an amide or a carboxyl group isconverted into a salt with a physiologically compatible base. As halidesaccording to general formula III, chlorine, bromine, iodine aresuitable, and as sulfonates, mesylate, tosylate and triflate aresuitable.

The reaction of the compound of general formula II with ahydroxylammonium salt is performed at temperatures of 0° C. to 100° C.,preferably at 25° C., in a solvent mixture that consists of an aproticsolvent, such as, e.g., tetrahydrofuran or pyridine, and a proticsolvent or solvent mixture, such as water and/or alcohols.

The etherification of the oximes with alkylating agents of generalformula III is carried out in a known way in an aprotic solvent orsolvent mixture, for example dimethylformamide or tetrahydrofuran ordimethoxyethane, under the action of a base at 0-30° C. As a base, forexample, sodium hydride is suitable.

The esterification of the alcohols of formula I (R₂ =H) is carried outin a way that is known in the art. For example, the esterification iscarried out in that an acid derivative, preferably an acid halide oracid anhydride, is reacted with an alcohol of formula I in the presenceof a base such as, for example, sodium hydride, pyridine, triethylamine,tributylamine or 4-dimethylaminopyridine. The reaction can be performedwithout a solvent or in an inert solvent, preferably acetone,acetonitrile, dimethylacetamide, dimethyl sulfoxide at temperaturesabove or below room temperature, for example, between -80° C. to 100°C., preferably at room temperature.

The reduction to the compounds of formula I with R₁ =CH₂ OH is performedwith a reducing agent that is suitable for the reduction of esters orcarboxylic acids, such as, for example, lithium aluminum hydride,diisobutyl aluminum hydride, etc. As a solvent, diethyl ether,tetrahydrofuran, dimethoxyethane, toluene, etc., are suitable. Thereduction is performed at temperatures of -30° C. up to boilingtemperature of the solvent, preferably 0° C. to 30° C.

The etherification of the alcohols of formula I (with R₁ =CH₂ OH and p=0and X=a direct bond) to compounds of general formula I (with X=0 andp=1-4) is carried out in a way that is known in the art. For example,the etherification is carried out in that the alcohol of general formulaI (R₁ =CH₂ OH), optionally after protection of present free hydroxygroups with a halocarboxylic acid derivative or haloalkyl derivative ofgeneral formula IV,

    Hal-(CH.sub.2).sub.p --R.sub.1                             (IV)

whereby Hal is a chlorine, bromine or iodine atom and R₁ has theabove-indicated meaning, is reacted in the presence of a base, and thenoptionally R₁, as described above, is further functionalized. Thereaction of the compound of general formula I with a halogen compound ofgeneral formula IV is performed at temperatures of 0° C. to 100° C.,preferably 10° C. to 80° C., in an aprotic solvent or solvent mixture,for example dimethyl sulfoxide, dimethylformamide, tetrahydrofuran,toluene, etc. As bases, the bases that are known to one skilled in theart for etherification are suitable, for example sodium hydride,potassium-tert-butylate, butyllithium. The above-mentionedetherification can also be performed preferably under phase-transferconditions with 20-50% aqueous sodium hydroxide or potassium hydroxidesolution without an additional solvent or in an aprotic solvent, suchas, for example, toluene in the presence of a phase-transfer catalystsuch as tetrabutylammonium hydrogen sulfate at temperatures of between0° C. and 90° C., preferably between 20° C. and 60° C.

The saponification of the esters of formula I is performed according tothe methods that are known to one skilled in the art, such as, forexample, with basic catalysts. The compounds of formula I can beseparated by the conventional separating methods into optical isomers(Asymmetric Synthesis, Vol. 1-5, Ed. J. D. Morrison, Academic Press,Inc., Orlando etc., 1985; Chiral Separations by HPLC, Ed. A. M.Krstulovic; John Wiley & Sons; New York etc. 1989).

The release of the protected hydroxyl groups is carried out according toknown methods. For example, the cleavage of hydroxyl protective groups,such as, for example, the tetrahydropyranyl radical, is performed in anaqueous solution of an organic acid, such as, e.g., oxalic acid, aceticacid, propionic acid, i.a., or in an aqueous solution of a mineral acid,such as, e.g., hydrochloric acid. To improve the solubility, awater-miscible inert organic solvent is suitably added. Suitable organicsolvents are, e.g., alcohols, such as methanol and ethanol, and ethers,such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran ispreferably used. The cleavage is performed preferably at temperatures ofbetween 20° C. and 80° C. The cleavage of the silyl ether protectivegroups is carried out, for example, with tetrabutylammonium fluoride orwith potassium fluoride in the presence of a crown ether (such as, forexample, dibenzo[18]-crown-6). As a solvent, for example,tetrahydrofuran, diethyl ether, dioxane, dichloromethane, etc., aresuitable. The cleavage is performed preferably at temperatures ofbetween 0° C. and 80° C.

The saponification of the acyl groups is carried out, for example, withalkali or alkaline-earth carbonates or -hydroxides in an alcohol or inthe aqueous solution of an alcohol. As an alcohol, lower aliphaticalcohols, such as, e.g., methanol, ethanol, butanol, etc., preferablymethanol, are considered. As alkali carbonates and -hydroxides,potassium, sodium and cesium salts can be mentioned. Preferred arepotassium salts.

As alkaline-earth carbonates and -hydroxides, for example, calciumcarbonate, calcium hydroxide and barium carbonate are suitable. Thereaction is carried out at -10° C. to +70° C., preferably at +25° C.

The introduction of ester group --COOR₄ for R₁, in which R₄ representsan alkyl group with 1-10 C atoms, is carried out according to themethods that are known to one skilled in the art. The 1-carboxycompounds are reacted, for example, with diazohydrocarbons in a way thatis known in the art. The esterification with diazohydrocarbons iscarried out, e.g., in that a solution of the diazohydrocarbon in aninert solvent, preferably in diethyl ether, is mixed with the 1-carboxycompound in the same solvent or in another inert solvent, such as, e.g.,methylene chloride. After the reaction is completed in 1 to 30 minutes,the solvent is removed, and the ester is purified in the usual way.Diazoalkanes are either known or can be produced according to knownmethods [Org. Reactions Vol. 8, pages 389-394 (1954)].

The introduction of ester group --COOR₄ for R₁, in which R₄ represents asubstituted or unsubstituted aryl group, is carried out according to themethods that are known to one skilled in the art. For example, the1-carboxy compounds are reacted in an inert solvent with thecorresponding arylhydroxy compounds with dicyclohexylcarbodiimide in thepresence of a suitable base, for example, pyridine,dimethylaminopyridine, triethylamine. As a solvent, methylene chloride,ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran,preferably chloroform, are suitable. The reaction is performed attemperatures of between -30° C. and +50° C., preferably at 10° C.

The leukotriene-B₄ derivatives of formula I with R₄ meaning a hydrogencan be converted into a salt with suitable amounts of the correspondinginorganic bases with neutralization. For example, in dissolving thecorresponding acids in water, which contains the stoichiometric amountof the base, the (solid inorganic) salt is obtained after water isevaporated or after a water-miscible solvent, e.g., alcohol or acetone,is added.

For the production of an ammonium salt, the free acid is dissolved in,e.g., a suitable solvent, for example, ethanol, acetone, diethyl ether,acetonitrile or benzene, and at least the stoichiometric amount of theamine is added to the solution. In this way, the salt usuallyaccumulates in solid form or is isolated after the solvent is evaporatedin the usual way.

The introduction of amide group --CONHR₅ with R₅ in the meaning ofalkanoyl is carried out according to the methods that are known to oneskilled in the art. The carboxylic acids of formula I (R₄ =H) are firstconverted into the mixed anhydride in the presence of a tertiary amine,such as, for example, triethylamine, with isobutyl chloroformate. Thereaction of the mixed anhydride with the alkali salt of thecorresponding amide or with ammonia (R₅ =H) is carried out in an inertsolvent or solvent mixture, such as, for example, tetrahydrofuran,dimethoxyethane, dimethylformamide, hexamethylphosphoric acid triamide,at temperatures of between -30° C. and +60° C., preferably at 0° C. to30° C. Another type of production of the amides involves the amidolysisof 1-ester (R₁ =COOR₄) with the corresponding amine.

Another possibility for the introduction of amide group --CONHR₅consists in the reaction of a 1-carboxylic acid of formula I (R₄ =H), inwhich free hydroxy groups are optionally intermediately protected, withcompounds of formula IV,

    O═C═N--R.sub.5                                     (IV)

in which R₅ has the above-indicated meaning.

The reaction of the compound of formula I (R₄ =H) with an isocyanate offormula IV is carried out optionally with the addition of a tertiaryamine, such as, e.g., triethylamine or pyridine. The reaction can beperformed without a solvent or in an inert solvent, preferablyacetonitrile, tetrahydrofuran, acetone, dimethylacetamide, methylenechloride, diethyl ether, toluene, at temperatures of between -80° C. to100° C., preferably at 0° C. to 30° C.

For the production of the other amides, for example, the desired acidanhydride can be reacted with ammonia or the corresponding amines.

If the starting product contains OH groups, these OH groups are alsobrought to reaction. If end products that contain free hydroxyl groupsare ultimately desired, a start is suitably made from starting productsin which the latter are intermediately protected by preferably readilycleavable ether or acyl radicals.

The separation of the diastereomers is carried out according to themethods that are known to one skilled in the art, for example by columnchromatography.

The compounds of general formula II that are used as starting materialcan be produced, for example, by an ester of general formula V ((a) K.Sakai et al., Tetrahedron 50, 3315 (1995); b) K. Koga et al.,Tetrahedron 49, 1579 (1993)), ##STR9## in which m and Y have theabove-indicated meanings, being ketalized with ethylene glycol, reducedwith diisobutylaluminum hydride and then oxidized to the aldehyde ofgeneral formula VI with the Collins reagent or by the Swern process(Tetrahedron Letters 34, 1651 (1978)) in a way that is known in the art.##STR10##

The Wittig-Horner olefination of aldehyde VI with the phosphonate offormula VII and a base and optionally subsequent hydrogenation as wellas subsequent reduction of the ester group, oxidation of the primaryalcohol, repeated Wittig-Horner olefination with the phosphonate offormula VII and optionally subsequent hydrogenation or a Wittig-Hornerreaction of aldehyde VI with a phosphonate of formula VIII provides theesters of general formula IX, whereby ##STR11## m, y and A have theabove-indicated meanings. As bases, for example,potassium-tert-butylate, diazabicyclononane, diazabicycloundecane orsodium hydride are suitable. Reduction of the ester group, for examplewith diisobutyl aluminum hydride, and subsequent oxidation of theprimary alcohol that is obtained, e.g., with manganese dioxide orCollins reagent, results in an aldehyde of formula X. ##STR12##

The organometallic reaction of the aldehyde of formula X with a Grignardreagent of formula XI, in which B, D

    X--Mg--B--D--R.sub.3                                       (XI)

and R₃ have the above-indicated meanings and X means chlorine, bromineor iodine, results, under protection of the hydroxy groups (for exampleby acylation) and optionally diastereomer separation, in the compoundsof formula XII. ##STR13##

The production of the compound of formula XI that is required for theorganometallic reaction is carried out by reaction of the correspondingterminal halide with magnesium. By reaction of ketal XII with diluteacetic acid and optionally saponification of the ester and subsequentsilylether formation, the ketone of formula XIII is obtained. ##STR14##

The compounds of formula XII, in which B means a CH₂ group and D means a--C.tbd.C group or a CH═CR₇ group, can be obtained, for example, by anorganometallic reaction of a propargyl halide and subsequent alkylationwith a corresponding alkyl halide and optionally subsequent Lindlarhydrogenation.

An alternative structure of the lower chain starts from the aldehyde offormula XIV, which resulted from the Wittig-Horner reaction of aldehydeVI and subsequent reduction and oxidation. ##STR15##

Wittig-Horner olefination of aldehyde XIV with a phosphonate of formulaXV ##STR16## and reduction of the ketone that is produced then resultedin an alcohol of formula XII, which optionally can be separated intodiastereomers. The protection of the hydroxy group that is now added,for example by acylation, ketal cleavage with acetic acid, optionallysaponification of the ester and silylether formation results in theketone of formula XIII.

The production of the phosphonates of general formula XV that arerequired for this reaction is described in, for example, DE 42 42 390 oris carried out in a way that is known in the art by reaction of an alkylhalide (that can be produced from the corresponding alcohol byhalogenation) of general formula XVI

    Hal-D--R.sub.3                                             (XVI)

with the dianion that is produced from the phosphonate of generalformula XVII ##STR17## in which B, D and R₃ have the above-indicatedmeanings.

An alternative access to the phosphonates of general formula XV consistsin the reaction of the anion of methylphosphonic acid dimethyl esterwith an ester of general formula XVIII,

    R.sub.9 OOC--B--D--R.sub.3                                 (XVIII)

in which R₃, B, and D have the above-indicated meanings and R₉ means analkyl group with 1-5 C atoms. These esters can be obtained by, forexample, alkylation with the corresponding halide.

The incorporation of the chemically and metabolically labile cis-Δ⁶,7double bond of LTB₄ into a cis-1,2-substituted cycloalkyl ring resultsin a stabilization, whereby especially by further derivatization of thefunctional groups and/or structural changes of the lower side chain,LTB₄ derivatives that can act as LTB₄ antagonists were obtained (DE-A 3917 597 and DE-A 42 27 790.6 and DE-A 41 08 351 and DE-A 41 39 886.8 andDE-A 42 42 390).

It has now been found that by introducing an alkyl group into the7-position and by introducing an oxime-ether unit into 5,6-position(numbering system beginning with a carboxyl-C atom with 1 when LTB₄nomenclature is used) in such leukotriene-B₄ derivatives, a prolongedduration of action, greater selectivity and better effectiveness can beachieved.

The compounds of formula I act in an antiinflammatory, antiallergic andantiproliferative manner. In addition, the compounds are suitable forlowering elevated triglyceride levels. In addition, they haveantimycotic properties. consequently, the new leukotriene-B₄ derivativesof formula I represent valuable pharmaceutical active ingredients. Thecompounds of formula I are suitable for topical and oral administration.

The new leukotriene-B₄ derivatives of formula I are suitable incombination with the additives and vehicles that are commonly used ingalenical pharmaceutics for topical treatment of diseases of the skin,in which leukotrienes play an important role, e.g.: contact dermatitis,eczemas of the most varied types, neurodermatoses, erythrodermia,pruritus vulvae et ani, rosacea, cutaneus lupus erythematosus,psoriasis, lichen ruber planus et verrucosis and similar skin diseases.

In addition, the new leukotriene-B₄ antagonists are suitable for thetreatment of multiple sclerosis and symptoms of shock.

The production of the pharmaceutical agent specialties is carried out inthe usual way by the active ingredients being converted with suitableadditives into the desired form of administration, such as, for example:solutions, ointments, creams or patches.

In the thus formulated pharmaceutical agents, the active ingredientconcentration depends on the form of administration. In lotions andointments, an active ingredient concentration of 0.0001% to 3% ispreferably used.

Further, the new compounds optionally in combination with commonly usedvehicles and adjuvants are also well-suited for the production ofinhalants, which can be used to treat allergic diseases of therespiratory system, such as, for example, bronchial asthma or rhinitis.

Further, the new leukotriene-B₄ derivatives are also suitable in theform of capsules, tablets or coated tablets, which preferably contain0.1 to 100 mg of active ingredient or are administered orally or in theform of suspensions, which preferably contain 1-200 mg of activeingredient per dosage unit, and are also administered rectally to treatdiseases of the internal organs, in which leukotrienes play an importantrole, such as, e.g.: allergic diseases of the intestinal tract, such ascolitis ulcerosa and colitis granulomatosa.

In these new forms of administration, the new LTB₄ derivatives, inaddition to the treatment of diseases of internal organs withinflammatory processes, are also suitable for the treatment of diseasesin which, leukotriene-dependent, the increased growth and the newformation of cells are important. Examples are leukemia (increasedgrowth of white blood cells) or arteriosclerosis (increased growth ofsmooth muscle cells of blood vessels).

The new leukotriene-B₄ derivatives can also be used in combination with,e.g., lipoxygenase inhibitors, cyclooxygenase inhibitors,glucocorticoids, prostacyclin agonists, thromboxane antagonists,leukotriene-D₄ antagonists, leukotriene-E₄ antagonists, leukotriene-F₄antagonists, phosphodiesterase inhibitors, calcium antagonists, PAFantagonists or other known forms of treatment of the respectivediseases.

The following embodiments are used for a more detailed explanation ofthe process according to the invention.

EXAMPLE 1

(7E)-7{(2S)-2-[(1E,3E,5S)-5-Hydroxy-9-phenyl-6,6-trimethylene-1,3-nonadien-8-inyl]-2-methylcyclohexylidene}-7-aza-6-oxaheptanoicacid-methyl ester

143 mg of(2S)-2-[(5S)-5-tert-butyldimethylsilyloxy-9-phenyl-6,6-trimethylene-1,3-nonadien-8-inyl]-2-methylcyclohexanoneis dissolved with 59 mg of hydroxylammonium sulfate in 3.5 ml ofmethanol, 3.5 ml of tetrahydrofuran and 3.5 ml of water, and it isstirred for 5 hours at room temperature. Then, the reaction mixture isconcentrated by evaporation in a vacuum, and the residue is taken up inether. It is washed with water and saturated sodium bicarbonatesolution, dried on sodium sulfate and concentrated by evaporation in avacuum. The residue is purified by chromatography on silica gel withhexane/ethyl acetate mixtures (gradient: 0-10% ethyl acetate). Yield:140 mg of the oxime as a colorless oil.

IR (film): 3277, 2930, 2857, 1598, 1490, 1462, 1442, 1360, 1255, 1119,1063, 992, 942, 836, 775, 755, 691 cm⁻¹.

17 mg of sodium hydride (60% dispersion in mineral oil) is added at roomtemperature to a solution of 140 mg of the above-described oxime in 5 mlof N,N-dimethylformamide, and it is stirred for 1 hour at roomtemperature. 82 mg of 5-bromovaleric acid-methyl ester is added to it.After two hours of stirring at room temperature, the batch is dilutedwith ether, washed with 10% citric acid, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-10% ethyl acetate). Yield: 160 mg of the ester as acolorless oil.

IR (Film): 2940, 2860, 1740, 1660, 1600, 1440, 1360, 1260, 1210, 1170,990, 840, 780, 760, 690 cm⁻¹.

410 mg of tetrabutylammonium-trihydrate is added to a solution of 160 mgof the above-described ester in 10 ml of tetrahydrofuran. After eighthours of stirring at room temperature, the batch is diluted with ether,washed with water, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ether mixtures (gradient: 0-40% ether). Yield: 82mg of the title compound as a colorless oil. This substance is thepreferred embodiment.

IR (Film): 3480, 2920, 2860, 1740, 1600, 1490, 1440, 1370, 1240, 1170,1090, 990, 920, 755, 690 cm⁻¹.

EXAMPLE 2

(7E)-7-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-9-phenyl-6,6-trimethylene-1,3-nonadien-8-inyl]-2-methylcyclohexylidene}-7-aza-6-oxaheptanoicacid

0.75 ml of 1N sodium hydroxide solution is added at room temperature toa solution of 68 mg of the ester, described in Example 1, in 0.8 ml ofmethanol and 0.8 ml of tetrahydrofuran. After six hours of stirring atroom temperature, the batch is acidified with 10% sulfuric acid andextracted with ethyl acetate. The combined organic extracts are washedwith saturated sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-50% ethyl acetate).

Yield: 52 mg of the title compound as a colorless oil.

IR (Film): 3440, 2920, 2860, 1710, 1600, 1490, 1440, 1370, 1240, 1090,1040, 990, 920, 840, 760, 695 cm⁻¹.

EXAMPLE 3

(7E)-7-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-7-aza-6-oxaheptanoicacid-methyl ester

730 mg of(2S)-2-[(5S)-5-tert-butyldimethylsilyloxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexanoneis stirred with 290 mg of hydroxylammonium sulfate in 20 ml of methanol,20 ml of tetrahydrofuran and 20 ml of water for 6 hours at roomtemperature. The reaction mixture is concentrated by evaporation in avacuum, and the residue is taken up in ether. It is washed with waterand saturated sodium bicarbonate solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-10% ethyl acetate). Yield: 700 mg of the oxime as acolorless oil.

IR (Film): 3280, 2930, 2860, 1740, 1600, 1490, 1470, 1460, 1440, 1370,1360, 1250, 1105, 1070, 990, 835, 810, 775, 755, 690 cm⁻¹.

24 mg of sodium hydride (60% dispersion in mineral oil) is added to asolution of 200 mg of the above-described oxime in 6 ml ofN,N-dimethylformamide. After one hour of stirring at room temperature,it is mixed with 120 mg of 5-bromovaleric acid-methyl ester. After twohours of stirring at room temperature, the batch is diluted with ether,washed with 10% citric acid, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ethyl acetate mixtures (gradient: 0-10% ethylacetate). Yield: 240 mg of the ester as a colorless oil.

IR (Film): 2920, 2860, 1740, 1600, 1490, 1440, 1360, 1255, 1200, 1170,1070, 990, 840, 775, 755, 690 cm⁻¹.

580 mg of tetrabutylammonium fluoride-trihydrate is added to a solutionof 230 mg of the above-described ester in 10 ml of tetrahydrofuran.After eight hours of stirring at room temperature, the batch is dilutedwith ether, washed with water, dried on sodium sulfate and concentratedby evaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ether mixtures (gradient: 0-40% ether). Yield:140 mg of the title compound as a colorless oil.

IR (Film): 3460, 2920, 2860, 1740, 1600, 1490, 1440, 1370, 1250, 1200,1170, 1100, 1070, 990, 920, 890, 760, 690 cm⁻¹.

EXAMPLE 4

(7E)-7{(2S)-2[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-7-aza-6-oxaheptanoicacid

1 ml of 1N sodium hydroxide solution is added at room temperature to asolution of 100 mg of the ester, described in Example 3, in 1.1 ml ofmethanol and 1.1 ml of tetrahydrofuran. It is stirred for 6 hours atroom temperature, acidified with 10% sulfuric acid and extracted withethyl acetate. The combined extracts are washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ethyl acetate mixtures (gradient: 0-50% ethylacetate). Yield: 96 mg of the title compound as a colorless oil.

IR (Film): 3400, 2920, 2860, 1710, 1600, 1490, 1440, 1370, 1240, 1070,990, 920, 760, 690 cm⁻¹.

EXAMPLE 5

(7E)-7-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-6,6-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-7-aza-6-oxaheptanoicacid-methyl ester

478 mg of(2S)-2-[(5S)-5-tert-butyldimethylsilyloxy-10-phenyl-6,6-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexanoneis stirred with 192 mg of hydroxylammonium sulfate in 13 ml of methanol,13 ml of tetrahydrofuran and 13 ml of water for 5 hours at roomtemperature. Then, the reaction mixture is concentrated by evaporationin a vacuum, and the residue is taken up in ether. It is washed withwater and saturated sodium bicarbonate solution, dried on sodium sulfateand concentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-10% ethyl acetate). Yield: 427 mg of the oxime as acolorless oil.

IR (Film): 3273, 2929, 2860, 1598, 1490, 1442, 1360, 1252, 1675, 993,942, 836, 775, 756, 692 cm⁻¹.

46 mg of sodium hydride (60% in mineral oil) is added at roomtemperature to a solution of 416 mg of the above-described oxime in 13ml of N,N-dimethylformamide. After one hour of stirring at roomtemperature, it is mixed with 241 mg of 5-bromovaleric acid-methylester. After two hours of stirring at room temperature, the batch isdiluted with ether, washed with 10% citric acid, dried on sodium sulfateand concentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-10% ethyl acetate). Yield: 410 mg of the ester as acolorless oil.

IR (Film): 2929, 2857, 2360, 1741, 1598, 1490, 1442, 1360, 1250, 1168,1056, 992, 836, 775, 756, 692 cm⁻¹.

393 mg of tetrabutylammonium fluoride-trihydrate is added to a solutionof 386 mg of the above-described ester in 2.5 ml of tetrahydrofuran.After eight hours of stirring at room temperature, the batch is dilutedwith ether, washed with water, dried on sodium sulfate and concentratedby evaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ether mixtures (gradient: 0-40% ether). Yield:241 mg of the title compound as a colorless oil.

IR (Film): 3476, 2931, 2840, 1738, 1491, 1442, 1372, 1169, 1070, 993,757, 692 cm⁻¹.

EXAMPLE 6

(7E)-7-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-6,6-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-7-aza-6-oxaheptanoicacid

9.8 ml of 0.5 N sodium hydroxide solution is added at room temperatureto a solution of 235 mg of the ester, described in Example 5, in 10 mlof methanol and 5 ml of tetrahydrofuran. After six hours of stirring atroom temperature, the batch is acidified with 10% sulfuric acid andextracted with ethyl acetate. The combined extracts are washed withsaturated sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-50% ethyl acetate).

Yield: 227 mg of the title compound as colorless oil.

IR (Film): 3440, 2930, 2860, 1710, 1600, 1490, 1440, 1370, 1240, 1180,1090, 1070, 1040, 990, 920, 890, 840, 760, 690 cm⁻¹.

EXAMPLE 7

(4E)-4-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexyliden}-4-aza-3-oxabutanoicacid

730 mg of(2S)-2-[(5S)-5-tert-butyldimethylsilyloxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexanoneis stirred with 290 mg of hydroxylammonium sulfate in 20 ml of methanol,20 ml of tetrahydrofuran and 20 ml of water for 5 hours at roomtemperature. Then, the reaction mixture is concentrated by evaporationin a vacuum, and the residue is taken up in ether. It is washed withwater and saturated sodium bicarbonate solution, dried on sodium sulfateand concentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-10% ethyl acetate). Yield: 700 mg of the oxime as acolorless oil.

IR (Film): 3280, 2930, 2860, 1740, 1600, 1490, 1470, 1460, 1440, 1370,1360, 1250, 1105, 1070, 990, 835, 810, 775, 755, 690 cm⁻¹.

28 mg of sodium hydride (60% dispersion in mineral oil) is added to asolution of 240 mg of the above-described oxime in 7 ml ofN,N-dimethylformamide. After one hour of stirring at room temperature,it is mixed with 120 mg of 2-bromoacetic acid-ethyl ester. After twohours of stirring at room temperature, the batch is diluted with ether,the organic phase is washed with 10% citric acid, dried on sodiumsulfate and concentrated by evaporation in a vacuum. The residue ispurified by chromatography on silica gel with hexane/ethyl acetatemixtures (gradient: 0-10% ethyl acetate). Yield: 230 mg of the ester asa colorless oil.

IR (Film): 2928, 2856, 2361, 1760, 1738, 1480, 1443, 1373, 1256, 1198,1103, 933, 890, 836, 775, 756, 692 cm⁻¹.

580 mg of tetrabutylammonium fluoride-trihydrate is added to a solutionof 220 mg of the above-described ester in 10 ml of tetrahydrofuran.After eight hours of stirring at room temperature, the batch is dilutedwith ether, washed with water, dried on sodium sulfate and concentratedby evaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ether mixtures (gradient: 0-40% ether). Yield: 94mg of the title compound as a colorless oil.

1 ml of 1N sodium hydroxide solution is added to a solution of 57 mg ofthe ester in 1 ml of methanol and 1 ml of tetrahydrofuran. After sixhours of stirring at room temperature, the batch is acidified with 10%sulfuric acid and extracted with ethyl acetate. The combined organicextracts are washed with saturated sodium chloride solution, dried onsodium sulfate and concentrated by evaporation in a vacuum. The residueis purified by chromatography on silica gel with hexane/ethyl acetatemixtures (gradient: 0-50% ethyl acetate). Yield: 62 mg of the titlecompound as a colorless oil.

IR (Film): 3440, 2920, 2860, 1700, 1600, 1490, 1440, 1370, 1310, 1090,1060, 990, 910, 760, 690 cm⁻¹.

EXAMPLE 8

(6E)-6-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-6-aza-5-oxahexanoicacid-methyl ester

730 mg of(2S)-2-[(5S)-5-tert-butyldimethylsilyloxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexanoneis stirred with 290 mg of hydroxylammonium sulfate in 20 ml of methanol,20 ml of tetrahydrofuran and 20 ml of water for 6 hours at roomtemperature. The reaction mixture is concentrated by evaporation in avacuum, and the residue is taken up in ether. It is washed with waterand saturated sodium bicarbonate solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-10% ethyl acetate). Yield: 700 mg of the oxime as acolorless oil.

IR (Film): 3280, 2930, 2860, 1740, 1600, 1490, 1470, 1460, 1440, 1370,1360, 1250, 1105, 1070, 990, 835, 810, 775, 755, 690 cm⁻¹.

18 mg of sodium hydride (60% dispersion in mineral oil) is added to asolution of 150 mg of the above-described oxime in 5 ml ofN,N-dimethylformamide. After one hour of stirring at room temperature,the batch is mixed with 78 mg of 4-bromobutyric acid-trimethylorthoesterand stirred for 2 hours at room temperature. It is diluted with ether,the organic phase is washed with 10% citric acid, dried on sodiumsulfate and concentrated by evaporation in a vacuum. The residue ispurified by chromatography on silica gel with hexane/ethyl acetatemixtures (gradient: 0-10% ethyl acetate). Yield: 180 mg of the ester asa colorless oil.

IR (Film): 2964, 2836, 1739, 1440, 1371, 1301, 1259, 1170, 1093, 961,916 cm⁻¹.

470 mg of tetrabutylammonium fluoride-trihydrate is added to a solutionof 180 mg of the above-described ester in 10 ml of tetrahydrofuran.After eight hours of stirring at room temperature, the batch is dilutedwith ether, washed with water, dried on sodium sulfate and concentratedby evaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ether mixtures (gradient: 0-40% ether). Yield:110 mg of the title compound as a colorless oil.

IR (Film): 3460, 2920, 2860, 1740, 1600, 1490, 1440, 1370, 1320, 1250,1200, 1170, 1090, 1050, 990, 950, 900, 760, 690 cm⁻¹.

EXAMPLE 9

(6E)-6-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-6-aza-5-oxahexanoicacid

0.8 ml of 1N sodium hydroxide solution is added to a solution of 75 mgof the ester, described in Example 8, in 0.8 ml of methanol and 0.8 mlof tetrahydrofuran. After six hours of stirring at room temperature, thebatch is acidified with 10% sulfuric acid and extracted with ethylacetate. The combined organic extracts are washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ethyl acetate mixtures (gradient: 0-50% ethylacetate).

Yield: 62 mg of the title compound as a colorless oil.

IR (Film): 3390, 2920, 1710, 1600, 1490, 1440, 1380, 1370, 1260, 1050,990, 760, 690 cm⁻¹.

EXAMPLE 10

(8E)-8-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexyliden}-8-aza-7-oxaoctanoicacid-methyl ester

2.14 g of(2S)-2-[(5S)-5-tert-butyldimethylsilyloxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexanoneis stirred with 860 mg of hydroxylammonium sulfate in 50 ml of methanol,50 ml of tetrahydrofuran and 50 ml of water for 5 hours at roomtemperature. Then, the reaction mixture is concentrated by evaporationin a vacuum and the residue is taken up in ether. It is washed withwater and saturated sodium bicarbonate solution, dried on sodium sulfateand concentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-10% ethyl acetate). Yield: 1.78 g of oxime as a colorlessoil.

IR (Film): 3280, 2930, 2860, 1740, 1600, 1490, 1470, 1460, 1440, 1370,1360, 1250, 1105, 1070, 990, 835, 810, 775, 755, 690 cm⁻¹.

24 mg of sodium hydride (60% dispersion in mineral oil) is added to asolution of 200 mg of the above-described oxime in 6 ml ofN,N-dimethylformamide. After one hour of stirring at room temperature,the batch is mixed with 133 mg of 6-bromohexanoic acid-ethyl ester.After two hours of stirring at room temperature, the reaction mixture isdiluted with ether, washed with 10% citric acid, dried on sodium sulfateand concentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-10% ethyl acetate). Yield: 260 mg of the ester as acolorless oil.

IR (Film): 2930, 2878, 1736, 1490, 1463, 1373, 1254, 1187, 1070, 992,836, 776, 756, 692 cm⁻¹.

630 mg of tetrabutylammonium fluoride-trihydrate is added to a solutionof 260 mg of the above-described ester in 12 ml of tetrahydrofuran.After eight hours of stirring at room temperature, the batch is dilutedwith ether, washed with water, dried on sodium sulfate and concentratedby evaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ether mixtures (gradient: 0-40% ether). Yield:160 mg of the title compound as a colorless oil.

IR (Film): 3460, 2925, 2860, 1740, 1600, 1490, 1440, 1370, 1160, 990,910, 760, 690 cm⁻¹.

EXAMPLE 11

(8E)-8-{(2S)-2-{(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexyliden}-8-aza-7-oxaoctanoicacid

1.31 ml of 1N sodium hydroxide solution is added to a solution of 129 mgof the ester, described in Example 10, in 1.4 ml of methanol and 1.4 mlof tetrahydrofuran. After six hours of stirring at room temperature, thebatch is acidified with 10% sulfuric acid and extracted with ethylacetate. The combined organic extracts are washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ethyl acetate mixtures (gradient: 0-50% ethylacetate).

Yield: 110 mg of the title compound as a colorless oil.

IR (Film): 3440, 2920, 2860, 1710, 1600, 1490, 1440, 1380, 1240, 1160,1090, 1050, 990, 920, 755, 690 cm⁻¹.

EXAMPLE 12

(7E)-7-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-7-aza-3,3-dimethyl-6-oxaheptanoicacid-methyl ester

1.3 g of(2S)-2-[(5S)-5-tert-butyldimethylsilyloxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexanoneis mixed with 522 mg of hydroxylammonium sulfate in 30 ml of methanol,30 ml of tetrahydrofuran and 30 ml of water. After five hours ofstirring at room temperature, the reaction mixture is concentrated byevaporation in a vacuum, and the residue is taken up in ether. It iswashed with water and saturated sodium bicarbonate solution, the organicphase is dried on sodium sulfate and concentrated by evaporation in avacuum. The residue is purified by chromatography on silica gel withhexane/ethyl acetate mixtures (gradient: 0-20% ethyl acetate).

Yield: 1.14 g of the oxime as a colorless oil.

IR (Film): 3270, 2930, 2850, 1740, 1660, 1600, 1490, 1470, 1460, 1440,1390, 1370, 1360, 1250, 1070, 1050, 990, 940, 835, 810, 775, 755, 690cm⁻¹.

47 mg of sodium hydride (60% dispersion in mineral oil) is added to asolution of 400 mg of the above-described oxime in 5 ml ofN,N-dimethylformamide. After one hour of stirring at room temperature,the batch is mixed with 265 mg of 5-bromo-3,3-dimethylpenantoicacid-methyl ester (see Example 12a) and stirred for 2 hours at roomtemperature. Then, it is diluted with ether, washed with 10% citricacid, dried on sodium sulfate and concentrated by evaporation in avacuum. The residue is purified by chromatography on silica gel withhexane/ethyl acetate mixtures (gradient: 0-10% ethyl acetate). Yield:350 mg of the ester as a colorless oil.

IR (Film): 2929, 2857, 1738, 1558, 1540, 1506, 1490, 1472, 1361, 1255,1073, 992, 937, 836, 775, 756, 692 cm⁻¹.

779 mg of tetrabutylammonium fluoride-trihydrate is added to a solutionof 320 mg of the above-described ester in 10 ml of tetrahydrofuran.After eight hours of stirring at room temperature, the batch is dilutedwith ether, washed with water, dried on sodium sulfate and concentratedby evaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ether mixtures (gradient: 0-40% ether). Yield:250 mg of the title compound as a colorless oil.

IR (Film): 3452, 2929, 2825, 1738, 1658, 1598, 1547, 1513, 1490, 1442,1371, 1224, 1126, 1042, 991, 925, 757, 692 cm⁻¹.

EXAMPLE 12a)

5-Bromo-3,3-dimethylpentanoic acid-methyl ester

18 g of sodium borohydride is suspended in 480 ml of 2-propanol. After30 hours of stirring at room temperature, a solution of 48 g of dimethylglutaric acid anhydride in 320 ml of 2-propanol is added in drops to it.The reaction mixture is refluxed for 2.5 hours. Then, it is concentratedby evaporation in a vacuum, the residue is poured on ice, acidified withconcentrated hydrochloric acid to pH 2 and stirred for 1 hour at roomtemperature and for 30 minutes at 80° C. It is extracted with ether, thecombined extracts are washed with saturated sodium bicarbonate solutionand saturated sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue is purified byvacuum distillation (150° C./12 mbar). Yield: 24 g of the lactone as acolorless oil.

IR (Film): 2960, 2870, 1730, 1600, 1485, 1470, 1405, 1370, 1315, 1255,1175, 1140, 1080, 1040, 1010, 990, 955, 890, 825, 665 cm⁻¹.

16 g of hydrogen bromide is introduced into 49 g of acetic acid at 10°C.-23° C. Then, 7 g of the lactone that is produced above in 5 ml ofacetic acid is added to it. After 72 hours of stirring at roomtemperature, the batch is poured onto ice water. The crystals aresuctioned off and dissolved in dichloromethane. The solution is dried onsodium sulfate and concentrated by evaporation in a vacuum. The residueis purified by crystallization from hexane.

Yield: 6.9 g of the bromide as white crystals. IR (Film): 2970, 2880,1710, 1460, 1410, 1390, 1370, 1305, 1250, 1180, 1130, 1090, 1040, 990,950, 665, 630 cm⁻¹.

An ethereal diazomethane solution is slowly added in drops at 0° C.under nitrogen to a solution of 1 g of the bromide, described above, in10 ml of ether until no more gas generation can be detected. Then, thebatch is concentrated by evaporation in a vacuum. The residue ispurified by chromatography on silica gel with hexane/ether mixtures(gradient: 0-40% ether). Yield: 1 g of the title compound as a colorlessoil.

EXAMPLE 13

(7E)-7-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexyliden}-7-aza-3,3-dimethyl-6-oxa-heptanoicacid

2.3 ml of 1N sodium hydroxide solution is added to a solution of 250 mgof the ester, described in Example 12, in 3 ml of methanol and 4 ml oftetrahydrofuran. After six hours of stirring at room temperature, thebatch is acidified with 10% sulfuric acid and extracted with ethylacetate. The combined extracts are washed with saturated sodium chloridesolution, dried on sodium sulfate and concentrated by evaporation in avacuum. The residue is purified by chromatography on silica gel withhexane/ethyl acetate mixtures (gradient: 0-50% ethyl acetate).

Yield: 218 mg of the title compound as a colorless oil.

IR (Film): 3400, 2920, 2860, 1710, 1590, 1570, 1490, 1440, 1370, 1240,1120, 1090, 1040, 990, 920, 890, 755, 690 cm⁻¹.

EXAMPLE 14

(7E)-7-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-7-aza-3,6-dioxaheptanoicacid-tert-butyl ester

1.3 g of(2S)-2-[(5S)-5-tert-butyldimethylsilyloxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexanoneis stirred with 522 mg of hydroxylammonium sulfate in 30 ml of methanol,30 ml of tetrahydrofuran and 30 ml of water for 7 hours at roomtemperature. Then, the reaction mixture is concentrated by evaporationin a vacuum, and the residue is taken up in ether. It is washed withwater and saturated sodium bicarbonate solution, the organic phase isdried on sodium sulfate and concentrated by evaporation in a vacuum. Theresidue is purified by chromatography on silica gel with hexane/ethermixtures (gradient: 0-20% ether). Yield: 1.14 g of the oxime as acolorless oil.

IR (Film): 3270, 2930, 2850, 1740, 1660, 1600, 1490, 1470, 1460, 1440,1390, 1370, 1360, 1250, 1070, 1050, 990, 940, 835, 810, 775, 755, 690cm⁻¹.

83 mg of sodium hydride (60% dispersion in mineral oil) is added to asolution of 700 mg of the above-described oxime in 10 ml ofN,N-dimethylformamide. After one hour of stirring at room temperature,it is mixed with 347 mg of 2-bromoacetic acid-ethyl ester. After twohours of stirring at room temperature, the batch is diluted with ether,washed with 10% citric acid, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ether mixtures (gradient: 0-10% ether). Yield:740 mg of the ester as a colorless oil.

IR (Film): 2928, 2856, 2359, 1760, 1738, 1598, 1490, 1462, 1444, 1376,1256, 1198, 1103, 993, 891, 836, 775, 756, 692 cm⁻¹.

2.3 ml of diisobutylaluminum hydride (20% in toluene) is added to asolution of 730 mg of the above-described ester in 15 ml of toluene at-60° C. under nitrogen. After 40 minutes, 1 ml of isopropanol and 1 mlof water are added in drops to it. After two hours of vigorous stirringat room temperature, the precipitate is suctioned off and thoroughlywashed with ethyl acetate. The combined filtrates are concentrated byevaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ether mixtures (gradient: 0-40% ether). Yield:600 mg of the alcohol as a colorless oil.

IR (Film): 3471, 2926, 2860, 1598, 1490, 1443, 1361, 1256, 1044, 992,938, 836, 775, 756, 692 cm⁻¹.

0.86 ml of 2-bromoacetic acid-tert-butyl ester, 4 ml of 25% sodiumhydroxide solution and 36 mg of tetrabutylammonium hydrogen sulfate areadded to a solution of 590 mg of the above-described alcohol in 5 ml oftoluene. After 16 hours of stirring at room temperature, the batch isdiluted with ether, washed with saturated sodium chloride solution,dried on sodium sulfate and concentrated by evaporation in a vacuum. Theresidue is purified by chromatography on silica gel with hexane/ethermixtures (gradient: 0-20% ether). Yield: 610 mg of the ester as acolorless oil.

IR (Film): 2929, 2857, 1750, 1598, 1490, 1461, 1368, 1254, 1225, 1141,1071, 992, 936, 836, 776, 756, 692 cm⁻¹.

1.4 g of tetrabutylammonium fluoride trihydrate is added to a solutionof 580 mg of the above-described ester in 18 ml of tetrahydrofuran.After four hours of stirring at room temperature, the batch is dilutedwith ether, washed with water, dried with sodium sulfate andconcentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ether mixtures (gradient: 0-40%ether). Yield: 410 mg of the title compound as a colorless oil.

IR (Film): 3477, 2929, 2860, 1748, 1598, 1490, 1443, 1368, 1227, 1141,1070, 992, 941, 844, 757, 692 cm⁻¹.

EXAMPLE 15

(7E)-7-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-7-aza-3,6-dioxaheptanoicacid

3.6 ml of 1N sodium hydroxide solution is added to a solution of 390 mgof the ester, described in Example 14, in 4 ml of methanol and 4 ml oftetrahydrofuran. After six hours of stirring at room temperature, thebatch is acidified with 10% sulfuric acid and extracted with ethylacetate. The combined extracts are washed with saturated sodium chloridesolution, dried on sodium sulfate and concentrated by evaporation in avacuum. The residue is purified by chromatography on silica gel withhexane/ethyl acetate mixtures (gradient: 0-50% ethyl acetate).

Yield: 331 mg of the title compound as a colorless oil.

IR (Film): 3440, 2920, 2860, 1740, 1600, 1490, 1440, 1370, 1240, 1140,1070, 990, 940, 910, 755, 690 cm⁻¹.

EXAMPLE 16

4-[(3E)-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-3-aza-2-oxapropyl]benzoicacid-ethyl ester

2.1 g of(2S)-2-[(5S)-5-tert-butyldimethylsilyloxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexanoneis stirred with 860 mg of hydroxylammonium sulfate in 50 ml of methanol,50 ml of tetrahydrofuran and 50 ml of water for 5 hours at roomtemperature. Then, the reaction mixture is concentrated by evaporationin a vacuum, and the residue is taken up in ether. It is washed withwater and saturated sodium bicarbonate solution, the organic phase isdried on sodium sulfate and concentrated by evaporation in a vacuum. Theresidue is purified by chromatography on silica gel with hexane/ethylacetate mixtures (gradient: 0-10% ethyl acetate). Yield: 1.78 g of theoxime as a colorless oil.

IR (Film): 3280, 2930, 2860, 1740, 1600, 1490, 1470, 1460, 1440, 1370,1360, 1250, 1105, 1070, 990, 835, 810, 775, 755, 690 cm⁻¹.

24 mg of sodium hydride (60% dispersion in mineral oil) is added at roomtemperature to a solution of 200 mg of the above-described oxime in 6 mlof N,N-dimethylformide. After one hour of stirring at room temperature,the reaction mixture is mixed with 145 mg of 4-(bromomethyl)benzoicacid-ethylester and stirred for 2 hours at room temperature. Then, thebatch is diluted with ether, washed with 10% citric acid, dried onsodium sulfate and concentrated by evaporation in a vacuum. The residueis purified by chromatography on silica gel with hexane/ethyl acetatemixtures (gradient: 0-10% ethyl acetate). Yield: 200 mg of the ester asa colorless oil.

IR (Film): 2928, 2856, 1720, 1614, 1490, 1443, 1366, 1275, 1105, 1021,992, 836, 775, 756, 692 cm⁻¹.

470 mg of the tetrabutylammonium fluoride-trihydrate is added to asolution of 200 mg of the above-described ester in 10 ml oftetrahydrofuran. After eight hours of stirring at room temperature, thebatch is diluted with ether, washed with water, dried on sodium sulfateand concentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ether mixtures (gradient: 0-40%ether). Yield: 128 mg of the title compound as a colorless oil.

IR (Film): 3480, 2920, 2860, 1720, 1610, 1600, 1420, 1280, 1180, 1110,1060, 1020, 990, 890, 850, 760, 690 cm⁻¹.

EXAMPLE 17

4-[(3E)-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-3-aza-2-oxapropyl]benzoicacid

0.97 ml of 1N sodium hydroxide solution is added to a solution of 99 mgof the ester, described in Example 16, in 1 ml of methanol and 1 ml oftetrahydrofuran. After six hours of stirring at room temperature, thebatch is acidified with 10% sulfuric acid and extracted with ethylacetate. The combined organic extracts are washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ethyl acetate mixtures (gradient: 0-50% ethylacetate).

Yield: 86 mg of the title compound as a colorless oil.

IR (Film): 3440, 2920, 2860, 1740, 1690, 1610, 1600, 1580, 1440, 1420,1370, 1310, 1240, 1170, 1100, 1050, 1020, 990, 920, 890, 850, 760, 690cm⁻¹.

EXAMPLE 18

3-[(3E)-{(2S)-2-{(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-3-aza-2-oxapropyl]benzoicacid-methyl ester

730 mg of(2S)-2-[(5S)-5-tert-butyldimethylsilyloxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexanoneis stirred with 290 mg of hydroxylammonium sulfate in 20 ml of methanol,20 ml of tetrahydrofuran and 20 ml of water for 5 hours at roomtemperature. Then, the reaction mixture is concentrated by evaporationin a vacuum, and the residue is taken up in ether. It is washed withwater and saturated sodium bicarbonate solution, dried on sodium sulfateand concentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-10% ethyl acetate). Yield: 700 mg of the oxime as acolorless oil.

IR (Film): 3280, 2930, 2860, 1740, 1600, 1490, 1470, 1460, 1440, 1370,1360, 1250, 1105, 1070, 990, 835, 810, 775, 755, 690 cm⁻¹.

30 mg of sodium hydride (60% dispersion in mineral oil) is added to asolution of 250 mg of the above-described oxime in 5 ml ofN,N-dimethylformamide. After one hour of stirring at room temperature,it is mixed with 170 mg of 3-(bromomethyl)benzoic acid-methyl ester.Then, it is diluted with ether, washed with 10% citric acid, dried onsodium sulfate and concentrated by evaporation in a vacuum. The residueis purified by chromatography on silica gel with hexane/ethyl acetatemixtures (gradient: 0-10% ethyl acetate). Yield: 230 mg of the ester asa colorless oil.

IR (Film): 2920, 2860, 1730, 1600, 1490, 1440, 1430, 1160, 1290, 1250,1200, 1100, 1070, 990, 900, 840, 810, 775, 755, 720, 690 cm⁻¹.

550 mg of tetrabutylammonium fluoride-trihydrate is added to a solutionof 230 mg of the above-described ester in 10 ml of tetrahydrofuran.After eight hours of stirring at room temperature, the batch is dilutedwith ether, washed with water, dried on sodium sulfate and concentratedby evaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ether mixtures (gradient: 0-40% ether). Yield:121 mg of the title compound as a colorless oil.

IR (Film): 3480, 2920, 2850, 1720, 1590, 1480, 1440, 1430, 1360, 1280,1200, 1100, 990, 920, 900, 830, 755, 690 cm⁻¹.

EXAMPLE 19

3-[(3E)-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-3-aza-2-oxapropyl]benzoicacid

0.9 ml of 1N sodium hydroxide solution is added to a solution of 92 mgof the ester, described in Example 18, in 0.9 ml of methanol and 0.9 mlof tetrahydrofuran. After six hours of stirring at room temperature, itis acidified with 10% sulfuric acid and extracted with ethyl acetate.The combined organic extracts are washed with saturated sodium chloridesolution, dried on sodium sulfate and concentrated by evaporation in avacuum. The residue is purified by chromatography on silica gel withhexane/ethyl acetate mixtures (gradient: 0-50% ethyl acetate). Yield: 93mg of the title compound as a colorless oil.

IR (Film): 3400, 2920, 2860, 1690, 1610, 1590, 1490, 1440, 1370, 1260,1200, 1100, 1040, 990, 830, 755, 690, 660, 650 cm⁻¹.

EXAMPLE 20

4-[(3E)-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-3-aza-2-oxapropyl}1,3-thiazole

2.1 mg of(2S)-2-[(5S)-5-tert-butyldimethylsilyloxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexanoneis stirred with 860 mg of hydroxylammonium sulfate in 50 ml of methanol,50 ml of tetrahydrofuran and 50 ml of water for 5 hours at roomtemperature. Then, the reaction mixture is concentrated by evaporationin a vacuum, and the residue is taken up in ether. It is washed withwater and saturated sodium bicarbonate solution, dried on sodium sulfateand concentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-10% ethyl acetate). Yield: 1.78 mg of the oxime as acolorless oil.

IR (Film): 3280, 2930, 2860, 1740, 1600, 1490, 1470, 1460, 1440, 1370,1360, 1250, 1105, 1070, 990, 835, 810, 775, 755, 690 cm⁻¹.

48 mg of sodium hydride (60% dispersion in mineral oil) is added to asolution of 200 mg of the above-described oxime in 5 ml ofN,N-dimethylformamide. After one hour of stirring at room temperature,it is mixed with 240 mg of 4-(chloromethyl)thiazole-2-carboxylicacid-ethyl ester and stirred for 2 hours at room temperature. Then, itis diluted with ether, the organic phase is washed with 10% citric acid,dried on sodium sulfate and concentrated by evaporation in a vacuum. Theresidue is purified by chromatography on silica gel with hexane/ethylacetate mixtures (gradient: 0-10% ethyl acetate). Yield: 247 mg of theester as a colorless oil.

IR (Film): 2928, 2856, 1712, 1598, 1490, 1462, 1443, 1360, 1253, 1071,992, 876, 836, 775, 756, 692 cm⁻¹.

630 mg of tetrabutylammonium fluoride-trihydrate is added to a solutionof 247 mg of the above-described ester in 12 ml of tetrahydrofuran.After eight hours of stirring at room temperature, the batch is dilutedwith ether, washed with water, dried on sodium sulfate and concentratedby evaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ether mixtures (gradient: 0-40% ether). Yield: 82mg of the title compound as a colorless oil.

IR (Film): 3400, 2920, 2860, 1740, 1720, 1600, 1490, 1440, 1420, 1390,1300, 1100, 1070, 1060, 990, 920, 880, 840, 760, 690 cm⁻¹.

EXAMPLE 20a)

4-(Chloromethyl)thiazole-2-carboxylic acid-ethyl ester

500 mg of oxalic acid-ethyl ester-thioamide and 476 mg of1,3-dichloroacetone are dissolved in 10 N,N-dimethylformamide andrefluxed for 27 hours. Then, it is diluted with ether, washed withwater, dried on sodium sulfate and concentrated by evaporation in avacuum. As a residue, 610 mg of the title compound remains as acolorless oil.

IR (Film): 3105, 2983, 2359, 1716, 1507, 1459, 1391, 1368, 1303, 1255,1140, 1090, 1017, 970, 862, 758, 715, 656 cm⁻¹.

EXAMPLE 21

(6E)-6-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-6-aza-5-oxa-1,1,1-trifluorohexane

2.1 g of(2S)-2-{(5S)-5-tert-butyldimethylsilyloxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexanoneis stirred with 860 mg of hydroxylammonium sulfate in 50 ml of methanol,50 ml of tetrahydrofuran and 50 ml of water for 5 hours at roomtemperature. Then, the reaction mixture is concentrated by evaporationin a vacuum, and the residue is taken up in ether. It is washed withwater and saturated sodium bicarbonate solution, dried on sodium sulfateand concentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-10% ethyl acetate). Yield: 1.78 mg of the oxime as acolorless oil.

IR (Film): 3280, 2930, 2860, 1740, 1600, 1490, 1470, 1460, 1440, 1370,1360, 1250, 1105, 1070, 990, 835, 810, 775, 755, 690 cm⁻¹.

18 mg of sodium hydride (60% dispersion in mineral oil) is added to asolution of 150 mg of the above-described oxime in 5 ml ofN,N-dimethylformamide. After one hour of stirring at room temperature,the reaction mixture is mixed with 110 mg of4,4,4-trifluoro-1-iodobutane and stirred for 2 hours at roomtemperature. Then, it is diluted with ether, washed with 10% citricacid, dried on sodium sulfate and concentrated by evaporation in avacuum. The residue is purified by chromatography on silica gel withhexane/ethyl acetate mixtures (gradient: 0-10% ethyl acetate). Yield:170 mg of the ester as a colorless oil.

IR (Film): 2929, 2887, 1490, 1443, 1373, 1334, 1253, 1155, 1071, 1025,991, 836, 775, 756, 691 cm⁻¹.

430 mg of tetrabutylammonium fluoride-trihydrate is added to a solutionof 170 mg of the above-described ester in 10 ml of tetrahydrofuran.After eight hours of stirring at room temperature, the batch is dilutedwith ether, washed with water, dried on sodium sulfate and concentratedby evaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ether mixtures (gradient: 0-40% ether). Yield:130 mg of the title compound as a colorless oil.

IR (Film): 3440, 2970, 2860, 1740, 1660, 1600, 1490, 1440, 1370, 1330,1310, 1250, 1230, 1150, 1070, 1020, 990, 910, 890, 830, 755, 690, 660cm⁻¹.

EXAMPLE 22

(5E)-5-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-9-phenyl-6,6-trimethylene-1,3-nonadien-8-inyl]-2-methylcyclohexylidene}-5-aza-1,1-dimethoxy-4-oxapentane

1.4 g of(2S)-2-[(5S)-5-tert-butyldimethylsilyloxy-9-phenyl-6,6-trimethylene-1,3-nonadien-8-inyl]-2-methylcyclohexanoneis stirred with 591 mg of hydroxylammonium sulfate in 35 ml of methanol,35 ml of tetrahydrofuran and 35 ml of water for 5 hours at roomtemperature. Then, the reaction mixture is concentrated by evaporationin a vacuum, and the residue is taken up in ether. It is washed withwater and saturated sodium bicarbonate solution, the organic phase isdried on sodium sulfate and concentrated by evaporation in a vacuum. Theresidue is purified by chromatography on silica gel with hexane/ethylacetate mixtures (gradient: 0-10% ethyl acetate). Yield: 1.36 mg of theoxime as a colorless oil.

IR (Film): 3277, 2930, 2857, 1598, 1490, 1462, 1360, 1255, 1120, 1063,992, 942, 836, 775, 755, 691 cm⁻¹.

36 mg of sodium hydride (60% dispersion in mineral oil) is added to asolution of 300 mg of the above-described oxime in 6 ml ofN,N-dimethylformamide. After one-hour of stirring at room temperature,the batch is mixed with 223 mg of 3-bromopropionaldehyde-dimethylacetaland stirred for 2 hours at room temperature. Then, the reaction mixtureis diluted with ether, washed with 10% citric acid, dried on sodiumsulfate and concentrated by evaporation in a vacuum. The residue ispurified by chromatography on silica gel with hexane/ethyl acetatemixtures (gradient: 0-10% ethyl acetate). Yield: 304 mg of the ester asa colorless oil.

IR (Film): 2931, 2857, 1653, 1558, 1506, 1490, 1443, 1388, 1254, 1191,1125, 1057, 992, 836, 775, 756, 692 cm⁻¹.

797 mg of tetrabutylammonium fluoride-trihydrate is added to a solutionof 300 mg of the above-described ester in 10 ml of tetrahydrofuran.After eight hours of stirring at room temperature, the batch is dilutedwith ether, washed with water, dried on sodium sulfate and concentratedby evaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ether mixtures (gradient: 0-40% ether). Yield:209 mg of the title compound as a colorless oil.

IR (Film): 3460, 2930, 2860, 1650, 1620, 1600, 1490, 1440, 1390, 1370,1190, 1130, 1070, 1060, 990, 920, 760, 690 cm⁻¹.

EXAMPLE 23

(7E)-7-{(2S)-2-[(1E,3E,5S)-5-Hydroxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexylidene}-7-aza-6-oxaheptanoicacid-5-tetrazolymamide

2.1 g of(2S)-2-[(5S)-5-tert-butyldimethylsilyloxy-10-phenyl-7,7-trimethylene-1,3-decadien-9-inyl]-2-methylcyclohexanoneis stirred with 860 mg of hydroxylammonium sulfate in 50 ml of methanol,50 ml of tetrahydrofuran and 50 ml of water for 13 hours at roomtemperature. Then, the reaction mixture is concentrated by evaporationin a vacuum, and the residue is taken up in ether. It is washed withwater and saturated sodium bicarbonate solution, dried on sodium sulfateand concentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-10% ethyl acetate). Yield: 1.8 g of the oxime as acolorless oil.

IR (Film): 3270, 2930, 2850, 1740, 1660, 1600, 1490, 1470, 1460, 1440,1390, 1370, 1360, 1250, 1070, 1050, 990, 940, 835, 810, 775, 755, 690cm⁻¹.

40 mg of sodium hydride (60% dispersion in mineral oil) is added to asolution of 330 mg of the above-described oxime in 7 ml ofN,N-dimethylformamide. After one hour of stirring at room temperature,the batch is mixed with 191 mg of 5-bromovaleric acid-methyl ester andstirred for 2 hours at room temperature. Then, the reaction mixture isdiluted with ether, washed with 10% citric acid, dried on sodium sulfateand concentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-10% ethyl acetate). Yield: 380 mg of the ester as acolorless oil.

IR (Film): 2927, 2360, 1738, 1598, 1490, 1435, 1361, 1250, 1168, 1070,992, 836, 776, 756, 692 cm⁻¹.

2.5 ml of 1N sodium hydroxide solution is added to a solution of 380 mgof the above-described ester in 3 ml of methanol and 3 ml oftetrahydrofuran. After 16 hours of stirring at room temperature, thebatch is acidified with 1N sulfuric acid to pH 5 and extracted withether. The combined organic extracts are washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ethyl acetate mixtures (gradient: 0-50% ethylacetate). Yield: 280 mg of the acid as a colorless oil.

IR (Film): 2926, 1713, 1598, 1490, 1443, 1372, 1254, 1070, 992, 938,836, 775, 756, 691 cm⁻¹.

50 mg of 5-aminotetrazole and then 100 mg ofN,N'-dicyclohexylcarbodiimide in 0.6 ml of tetrahydrofuran are added toa solution of 260 mg of the above-described acid in 1.5 ml oftetrahydrofuran under nitrogen. After 20 hours at room temperature, theprecipitate is suctioned off and washed with ethyl acetate. The combinedfiltrates are concentrated by evaporation in a vacuum. The residue ispurified by chromatography on silica gel with hexane/ethylacetate/methanol mixtures (Gradient: 0-100% ethyl acetate, 0-10%methanol). Yield: 260 mg of the amide as a colorless oil.

IR (Film): 2930, 2860, 1700, 1630, 1600, 1540, 1440, 1400, 1370, 1310,1250, 1060, 990, 920, 840, 810, 780, 755, 740, 690 cm⁻¹.

975 mg of tetrabutylammonium fluoride trihydrate is added to a solutionof 260 mg of the above-described amide in 14 ml of tetrahydrofuran.After 8 hours at room temperature, the batch is diluted with ether,washed with water, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ether mixtures (gradient: 0-100% ether). Yield:131 mg of the title compound as a colorless oil.

IR (Film): 3220, 2930, 2860, 1700, 1630, 1590, 1540, 1490, 1450, 1400,1370, 1310, 1250, 1200, 1130, 1090, 1040, 990, 890, 840, 760, 740, 690cm⁻¹.

EXAMPLE 24

(7E)-7-{(2S)-2-[(1E,3E,5S)-6,6-Dimethyl-5-Hydroxy-9-phenoxy-1,3-nonadienyl]-2-methylcyclohexylidene}-7-aza-3,3-dimethyl-6-oxaheptanoicacid-methyl ester

485 mg of(2S)-2-[(5S)-5-tert-butyldimethylsilyloxy-6,6-dimethyl-9-phenoxy-1,3-nonadienyl]-2-methylcyclohexanoneis stirred with 295 mg of hydroxylammonium sulfate in 10 ml of methanol,10 ml of tetrahydrofuran and 10 ml of water for 5 hours at roomtemperature. Then, the reaction mixture is concentrated by evaporationin a vacuum, and the residue is taken up in ether. It is washed withwater and saturated sodium bicarbonate solution, dried on sodium sulfateand concentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/ethyl acetate mixtures(gradient: 0-10% ethyl acetate). Yield: 347 mg of the oxime as acolorless oil.

IR (Film): 3278, 2930, 2840, 1652, 1601, 1587, 1497, 1471, 1386, 1361,1301, 1247, 1171, 1109, 1062, 993, 942, 836, 775, 753, 691, 666 cm⁻¹.

40 mg of sodium hydride (60% dispersion in mineral oil) is added to asolution of 331 mg of the above-described oxime in 5 ml ofN,N-dimethylformamide. After one hour of stirring at room temperature,the batch is mixed with 223 mg of 5-bromo-3,3-dimethylpentanoicacid-methyl ester (Example 12a) and stirred for 2 hours at roomtemperature. Then, the reaction mixture is diluted with water, washedwith 10% citric acid, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ethyl acetate mixtures (gradient: 0-10% ethylacetate). Yield: 348 mg of the ester as a colorless oil.

IR (Film): 2956, 2840, 1738, 1600, 1498, 1471, 1386, 1247, 1110, 1043,992, 836, 775, 753, 691, 666 cm⁻¹.

4.1 g of tetrabutylammonium fluoride-trihydrate is added to a solutionof 339 mg of the above-described ester in 10 ml of tetrahydrofuran.After eight hours of stirring at room temperature, the batch is dilutedwith ether, washed with water, dried on sodium sulfate and concentratedby evaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ether mixtures (gradient: 0-40% ether). Yield:220 mg of the title compound as a colorless oil.

IR (Film): 3500, 2932, 2850, 2358, 1738, 1600, 1586, 1498, 1470, 1387,1246, 1172, 1040, 991, 928, 754, 692 cm⁻¹.

EXAMPLE 25

(7E)-7-{(2S)-[(1E,3E,5S)-6,6Dimethyl-5-Hydroxy-9-phenoxy-1,3-nonadienyl]-2-methylcyclohexylidene}-7-aza-3,3-dimethyl-6-oxaheptanoicacid

1.9 ml of 1N sodium hydroxide solution is added to a solution of 218 mgof the ester, described in Example 24, in 2 ml of methanol and 2 ml oftetrahydrofuran. After six hours of stirring at room temperature, thebatch is acidified with 10% sulfuric acid and extracted with ethylacetate. The combined organic extracts are washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. The residue is purified by chromatography onsilica gel with hexane/ethyl acetate mixtures (gradient: 0-50% ethylacetate).

Yield: 156 mg of the title compound as a colorless oil.

IR (Film): 3440, 2960, 2880, 1710, 1600, 1580, 1500, 1470, 1375, 1260,1190, 1160, 1040, 990, 930, 920, 760, 690 cm⁻¹.

In Vivo Test Systems

(i). Production of Human Polymorphonuclear Leukocytes (PMN)

PMNs of healthy volunteers are isolated from heparinized venous blood bydextran sedimentation and subsequent centrifuging viaFicoll-Histopaque®. The remaining erythrocytes are eliminated byhypotonic lysis in 0.2% sodium chloride solution. The PMNs areresuspended in Hank's balanced salt solution (HBSS) and mixed with eggalbumin (OVA) or bovine serum albumin (BSA).

(ii). LTB4-Receptor-Competition-Binding Test

Human PMNs are incubated together with OVA with tritium-labeledleukotriene-B₄ (LTB₄) in the presence or absence of the testedsubstances at concentrations of 10 μmol/l to 0.05 mmol/l in HBSS.Cell-bonded, tritium-labeled LTB₄ is separated from the free ligands byvacuum filtration by a glass fiber filter and measured in ascintillation measuring device. The non-specific binding oftritium-labeled LTB₄ is determined in the presence of excess unlabeledLTB₄ (500 nmol/l). Competition factor (CF) is calculated from the ratioof the concentration of the substance to the concentration of the LTB₄,which results in a 50% reduction of the tritium-labeled LTB₄ -receptorbond.

(iii). LTB₄ -induced Chemotaxis Test

The chemotaxis test is carried out with modified Boyden chambers, whichconsist of Transwell® modules with polyvinylpyrrolidone-clad polycarbonfilters with a pore size of 3 μm. The upper chamber part contains thehuman PMNs in HBSS, which is supplemented with BSA or OVA. The lowerchamber part is to be added with just buffer or with the chemotacticallyactive leukotriene B₄ (LTB₄) at a concentration within the limits of 1nmol/l to 100 nmol/l in the presence or absence of the test substance.The chamber is incubated for 60 minutes in water-saturated atmospherewith 5% carbon dioxide. The number of PMNs, which have found their wayinto the lower chamber part, is determined in a calibrated test by themeasurement of the activity of the enzyme myeloperoxidase (MPO). Theenzyme activity is measured by spectrometry (450 nm) by determining therate of H₂ O₂ -dependent oxidation of aromatic amine3,3',5,5'-tetramethylbenzidine (TMB).

The EC₅₀ value is determined graphically by the non-linear regressioncurve. The K_(B) value describes the capabilities of the competitiveantagonist. The K_(B) value is determined as the antagonistconcentration that is necessary to raise the EC₅₀ value of the agonistby a factor of 2.

The K_(B) value is calculated as follows:

    K.sub.B =[LTB.sub.4 -receptor-antagonist]/(DR-1)

(DR)=the ratio of the LTB₄ concentration that is required forhalf-maximum stimulation in the presence of the antagonist, to the LTB₄concentration that is required for half-maximum stimulation in theabsence of the antagonist.)

(iv). LTB₄ /iloprost-induced Skin Inflammation in the Ears of Mice

Female NMRI mice with a weight of 26 to 28 g and an age of 5 to 6 weeksare used for this in viva experiment. Ten animals per group are dividedat random and kept separate in the various treatment groups. The animalshad free access to food and water. To prevent the oral absorption ofLTB₄ /iloprost solutions that are to be administered topically,restraining collars are fastened around the necks of the animals underether anesthesia shortly before the topical application.

Leukotriene B₄ (LTB₄) and the stable prostacyclin derivative iloprost isdissolved in ethanol/isopropyl myristat (95+5 v/v) at a concentration of0.003% (w/v). 10 μl of the LTB₄ /iloprost solution is administeredtopically on the outside surface of each ear (surface area about 1 cm²/ear). This corresponds to a dose of 0.3 μg per ear or about 0.3 μg percm². Animals that are treated with just LTB₄ /iloprost solution developthe typical features of an inflamed skin with the formation of edemasand infiltration of neutrophiles. These animals are used as positivecontrol animals, that were treated with just ethanol/isopropyl myristat(95+5 v/v) on the outside surface of each ear (surface area of about 1cm² /ear), are used as a negative control.

The effect of the LTB₄ -receptor-antagonists on the LTB₄/iloprost-induced inflammation reaction is determined either with atopical administration or with an intragastric administration of thetest substance.

For the topical application the test substance is dissolved in anLTB4/iloprost solution at various concentrations. 10 μl of this solutionis applied topically on the outside surface of the ear.

For intragastric administr ation, the LTB4-receptor-antagonist isdissolved in ethanol. Immediately after the topical administration withLTB4/iloprost, the LTB4-receptor-antagonist or only the solvent isadministered intragastrically at various doses with the aid of a probe.The maximum final concentration of ethanol is 3%. The amount of ethanoldecreases with additional dilution steps.

The animals are sacrificed 24 hours after the inflammatory reaction setsin. The ears are separated, weighed, flash-frozen and stored for otherstudies. The peroxidase activity is determined by spectrometry in thehomogenate of the ear skin. The tissue is homogenized in HTAB buffer(0.5% hexadecyltrimethylammonium bromide (w/v) in 10⁻³ Mol/l of3-[N-morpholino]propanesulfonic acid with pH 7.0) for 20 seconds with aPolytron® PT 3000 (Kinematica AG, Switzerland) at a rotation of 30,000rpm. The homogenate is centrifuged for 20 minutes at 10° C. and at14,500 rpm (20,000 g) in a Sorvall RC2-B centrifuge (SM-24 rotor). Theaqueous supernatant is suctioned off and its peroxidase activity istested at a dilution of 1 to 50 in HTAB buffer. The peroxidase activityis determined by photometric measurement of the rate of H₂ O₂ -dependentoxidation of the aromatic amine 3,3',5,5'-tetramethylbenzidine (TMB). Ina 96-hole microtiter plate, the dilute supernatants are incubated withTMB solution and hydrogen peroxide (solution of 6.5 mg of3,3',5,5'-tetramethylbenzidine dihydrochloride in 1 ml of dimethylsulfoxide (DMSO); 1:100 (v/v), dissolved with 0.1 mol/l ofsodium-acetate-citrate buffer, pH 6.0, final concentration in theincubation mixture: 1.57 •10⁻⁴ mol/l) (hydrogen peroxide 30% H202 1:16860 (v/v) dissolved with 0.1 mol/l of sodium-acetate-citrate-buffer,pH 6.0, final concentration in the incubation mixture: 4.93•10⁻⁵ mol/l).After 30 minutes at room temperature, the reaction is stopped by adding0.5 mol/l of sulfuric acid. The extinction is determined at 450 nm(maximum absorption) in a microtiter-plate measuring device.

What is claimed is:
 1. Leukotriene-B₄ derivatives of general formula I##STR18## in which R₁ represents H, CF₃, CH₂ OH, COOR₄, CONR₅ R₆, andR₂represents H or an organic acid radical with 1-15 C atoms, R₃ symbolizesH; C₁ -C₁₄ alkyl, C₃ -C₁₀ cycloalkyl optionally substituted in one ormore places; C₆ -C₁₀ aryl radicals, independently of one another,optionally substituted in one or more places by halogen, phenyl, C₁ -C₄alkyl, C₁ -C₄ alkoxy, fluoromethyl, chloromethyl, trifluoromethyl,carbonyl, carboxyl or hydroxyl; or a 5- to 6-membered aromaticheterocyclic ring with at least 1 heteroatom, R₄ means hydrogen, C₁ -C₁₀alkyl, C₃ -C₁₀ cycloalkyl; C₆ -C₁₀ aryl radicals optionally substitutedby 1-3 halogen, phenyl, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, fluoromethyl,chloromethyl, trifluoromethyl, carboxyl or hydroxyl; CH₂ --CO--(C₆ -C₁₀)aryl or a 5- to 6-membered ring with at least 1 heteroatom, A symbolizesa trans, trans--CH═CH--CH═CH, a --CH₂ CH₂ --CH═CH-- or a tetramethylenegroup, B symbolizes a C₁ -C₁₀ straight-chain or branched-chain alkylenegroup, which optionally can be substituted by fluorine or the group##STR19## D means a direct bond, oxygen, sulfur, --C.tbd.C--, --CH═CR₇,or together with B can also mean a direct bond, R₅ and R₆ are the sameor different, and represent H or C₁ -C₄ alkyl optionally substituted byhydroxyl groups, or R₆ represents H and R₅ represents C₁ -C₁₅ alkanoylor R₈ SO₂, R₇ means H, C₁ -C₅ alkyl, chlorine, bromine, R₈ has the samemeaning as R₃, m means 1-3, o means 0-5, p means 0-5, X is a directbond, oxygen, sulfur, an aromatic compound or heteroaromatic compound, Yis a C₁ -C₈ alkyl optionally substituted in one or more places, C₃ -C₁₀cycloalkyl, optionally substituted by aryl, n is 2-5,and, if R₄ meanshydrogen, their salts with physiologically compatible bases and theircyclodextrin clathrates.
 2. Pharmaceutical preparations characterized bya content of leukotriene-B₄ derivatives of general formula I accordingto claim
 1. 3. Process for the production of leukotriene-B₄ derivativesof general formula I, according to claim 1, characterized in that aketone of formula II ##STR20## in which A, B, D, m, R₂, R₃ and Y havethe above-indicated meanings, optionally under protection of freehydroxyl groups in R₂, is reacted with a hydroxylamine or ahydroxylammonium salt and then with an alkylating reagent of generalformula III,

    E--(CH.sub.2).sub.o --X--(CH.sub.2).sub.p --R.sub.1        (III)

whereby E represents a halide or sulfonate, and o, X, p, and R₁ have theabove-indicated meanings, is reacted in the presence of a base andoptionally then separated in any sequence of isomers, protected hydroxylgroups are released and/or a free hydroxyl group is etherified and/or acarboxyl group is reduced and/or a carboxyl group is esterified and/or acarboxyl group is converted into an amide or a carboxyl group isconverted into a salt with a physiologically compatible base.